Abstract Body (Do not enter title and authors here): Background: Women with diabetes have a 50% higher risk of ASCVD than men. HDL particle concentration (HDL-p) is inversely associated with ASCVD risk. Previously, we showed that women's typically higher HDL-p levels diminish during diabetes development. Here, we examined HDL-p's role in the sex disparity in ASCVD risk among individuals with diabetes.

Methods: We pooled data from the Multi-Ethnic Study of Atherosclerosis (MESA, n=6761) and the Dallas Heart Study (DHS, n=1794), including ASCVD-free individuals with diabetes (n=1006), prediabetes (n=1232), or normal glucose (n=6167). Incident ASCVD included coronary heart disease (CHD: myocardial infarction, CHD death, revascularization) and ischemic stroke. We used Cox proportional hazards models to examine the association between HDL-p (by tertile and per SD) and ASCVD risk, adjusting for age, race, education, smoking, alcohol use, physical activity, BMI, systolic blood pressure, HDL-cholesterol (HDL-c), lipid-lowering medication, fasting glucose, fasting insulin, menopausal status (women only), and cohort. Analyses were stratified by sex and glycemic status.

Results:
Over a median 19-year follow-up, 274 ASCVD events (200 CHD and 74 strokes) occurred among 1006 individuals with diabetes. In the adjusted models, lower HDL-p was significantly associated with higher ASCVD risk in women with diabetes, but not in men with diabetes (Figure 1). When evaluating CHD and strokes separately, sex-specific patterns persisted in people with diabetes: a 1 SD lower HDL-p was associated with higher risk in women (CHD HR 1.5 [1.0–2.0], stroke HR 1.3 [0.9–2.1]) but not in men (CHD HR 0.8 [0.5–1.8], stroke HR 1.1 [0.8–1.5]); P for sex interaction=0.09. The sex differential associations were not observed in prediabetes (206 ASCVD events among 1232 individuals) or normal glucose (781/6179) groups.

Conclusions:
HDL-p is more strongly associated with an increased risk of ASCVD in women with diabetes than in men with diabetes, independent of HDL-c and other traditional risk factors. In diabetes, altered HDL metabolism, characterized by reduced HDL-p, contributes to the heightened ASCVD risk observed in female patients.